tbuckley/cabot-search huggingface dataset:
Comparative secretome analysis of obese perivascular adipose tissue reveals impaired adipose-neuronal crosstalk
Authors: E Duregotti, C Reumiller, U Mayr, M Hasman, L Schmidt, S A Burnap, K Theofilatos, J Barallobre-Barreiro, A Viviano, M Jahangiri, M Mayr
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): BHF Programme Grant (RG/16/14/32397) VASCage-Research Center on Vascular Ageing and Stroke (No. 868624) Background While canonical adipose tissue (AT) depots have been extensively characterised in health and disease, comparatively little is known about the pathological changes affecting the perivascular AT’s (PVAT) physiology during obesity. Purpose The aim of this study was to study the impact of obesity on the secretory activity of the murine PVAT. Methods We exploited proteomics to profile the secretome of peri-aortic and canonical AT depots in wild-type (wt) and obese (ob/ob) mice. In parallel, fat tissues were processed for biochemical and histological analysis and mechanistical experiments were performed in vitro on primary neuronal cultures. Results Proteomics on ATs conditioned media from wt mice revealed that each fat depot displays a unique secretory profile. The enrichment of neuronal cell-adhesion molecules detected in PVAT secretomes reflected a higher content of intra-parenchymal sympathetic projections compared to non-perivascular ATs. A significant decrease of the same neuronal proteins in PVAT conditioned media from ob/ob mice was found to be associated with a substantial reduction of the perivascular sympathetic innervation. Intriguingly, a similar decrease of sympathetic markers was detected in the epicardial AT from obese patients. Mechanistically, the conditioned media from ob/ob AT explants was found to exert a deleterious effect on the axons of primary sympathetic neurons in vitro, indicating that this neuropathy is due to local alterations of the PVAT secretome that detrimentally impact on the embedded sympathetic neurites. Among proteins significantly down-regulated in the secretomes of ob/ob PVAT samples, neuronal growth regulator 1 (Negr1) was found to promote axonal elongation and branching on sympathetic neurons in vitro. Administration of recombinant Negr1 also partially restored the neurotrophic effect of ob/ob AT secretomes on sympathetic axons both in vitro and in vivo. Conclusions Obesity-related alterations in the secretome of PVAT severely affect the homeostasis of the perivascular environment, leading to a loss of perivascular sympathetic innervation. A novel neurotrophic role is unveiled for Negr1, whose locus has been associated with human obesity.
A real-world assessment of genomic testing and treatment in stage 4 gastric cancer patients.
Authors: Therese Conner, Roy Arguello, Arturo Loaiza-Bonilla, Robert S Hauser, Barbara Harris, Jackeline Cruz
Journal: Journal of Clinical Oncology (2022)

e16007 Background: In gastric cancer, genomic testing plays an important role in treatment decisions that could improve response and extend life. While advanced therapies are recommended for certain patients, little is known about the frequency of real-world testing and treatment in metastatic disease. This study sought to assess the incidence and results of genomic testing among metastatic gastric cancer patients in the United States. Methods: This retrospective study used de-identified electronic health record data from adult Stage 4 gastric and gastroesophageal junction (GEJ) adenocarcinoma patients who received treatment at Cancer Treatment Centers of America (CTCA) from 2016-2021. Results: Among 238 patients, 172 had gastric and 67 had GEJ cancer. Mean age at diagnosis was 56 years (SD = 10.5), 64% were male, and 68% were Caucasian. Of 238, 101 (42%) received genomic testing at CTCA, 113 days (median) post-diagnosis. 49 (21%) were HER2+; 89 (37%) had PD-L1 testing, of which 67 (75%) were &gt; 1%. Four (2%) had tumor mutation burden (TMB) &gt;10 (high). Among 48 (20%) patients who received trastuzumab, 85% started in 1 st line, and 97% of cycles were combination therapy. Of the 33 patients who received pembrolizumab, 97% started in 2 nd line; 79% started prior to 2020 and 94% of cycles were monotherapy. Conclusions: In stage 4 gastric cancers, this study found that almost half of patients received genomic testing within the first year of diagnosis. Percentages of patients with gene amplification were within ranges of similar studies. Timing of trastuzumab and pembrolizumab was in accordance with guidelines. Most patients initiated pembrolizumab prior to 2020, suggesting early adoption of use. Cost-utility analyses of treatment options may be warranted in future research.[Table: see text]
Benefits, harms, and burden of colorectal cancer screening among childhood cancer survivors previously treated with abdominal-pelvic radiation.
Authors: Jennifer M Yeh, Claudia L. Seguin, Jillian Whitton, Wendy M. Leisenring, Gregory T. Armstrong, Tara O. Henderson, Melissa M. Hudson, Paul C. Nathan, Joseph Philip Neglia, Kevin C. Oeffinger, Lisa Diller, Amy B Knudsen
Journal: Journal of Clinical Oncology (2022)

10015 Background: Survivors of childhood cancer treated with abdominal-pelvic radiation are at increased risk for colorectal cancer (CRC). The Children’s Oncology Group recommends early initiation of CRC screening at age 30, yet the benefits and burden are unknown. Methods: We used incidence and mortality data from the Childhood Cancer Survivor Study to modify the SimCRC model from the Cancer Intervention and Surveillance Modeling Network (CISNET) to reflect high CRC and competing mortality risks among survivors, assuming the elevated cancer risk arises from higher adenoma onset. Strategies evaluated varied by modality (no screening, colonoscopy, multitarget stool DNA [mtsDNA] testing, fecal immunochemical testing [FIT]), screening start age (25, 30, 35, 40, 45) and screening interval (every 3, 5 or 10 yrs for colonoscopy; every 1, 2 or 3 yrs for mtsDNA and FIT). Abnormal stool test results were followed up with colonoscopy. Screening performance and complication rates were based on published studies. Analyses assumed full uptake and adherence to all screening and follow-up procedures. To identify the optimal strategy for each modality, we estimated the number of colonoscopies required per additional life-year gained and compared it to benchmarks for screening strategies recommended by the US Preventive Services Task Force for average-risk individuals. Results: Among a simulated cohort of 20-yr-old 5-yr survivors with a history of abdominal-pelvic radiation, the cumulative CRC risk at age 50 was 0.8%, approximately twice that predicted among general population average-risk individuals (0.4%). In the absence of screening, 73 per 1000 survivors would be diagnosed with CRC in their lifetime and 29 would die from the disease. All screening strategies evaluated were estimated to yield substantial reductions in the lifetime number of CRC cases (45-71 cases averted per 1000) and deaths (23-28 deaths averted per 1000). The estimated lifetime number of colonoscopies ranged from 1781 to 14,625 per 1000. The lifetime number of colonoscopy complications was relatively low at 9 to 20 per 1000. Based on the burden-to-benefit ratios, colonoscopy every 10 yrs starting at age 30, mtsDNA every 3 yrs starting at age 30, or FIT every 3 yrs starting at age 25 were the optimal screening strategies identified (Table). Conclusions: Early initiation of screening may substantially reduce CRC mortality among high-risk childhood cancer survivors. These estimates of the balance of screening benefits and burden can inform follow-up care guidelines. [Table: see text]
Influence of decision support persons on breast cancer treatment decisions among Latinas.
Authors: Krystal A Morales, Paul Abrahamse, Christine M Veenstra, Sarah T. Hawley, Reshma Jagsi, Lauren P. Wallner
Journal: Journal of Clinical Oncology (2022)

12025 Background: Prior studies suggest that decision support persons (DSPs) involvement in breast cancer promotes greater deliberation and decision quality. Despite having the highest level of involvement, Latinx DSPs report the lowest satisfaction with their involvement. The reasons for this remain unknown. We examined the treatment decision-making experiences of Latinx DSPs, their influence on treatment deliberation, subjective decision quality (SDQ), and treatment received. Methods: Women with newly diagnosed early-stage breast cancer as reported to the Surveillance, Epidemiology, and End Results (SEER) registries of Georgia and Los Angeles County in 2014-2015 were surveyed. Participants identified the DSPs who played a key role in treatment decisions, who were also surveyed. We examined: (1) bivariate associations of DSP characteristics (e.g type, age, race/ethnicity, education, acculturation level) with DSP-reported level of engagement (informed about decisions, involvement (extent and satisfaction), and aware of patient preferences), (2) DSP engagement with patient-reported SDQ and treatment deliberation using multivariable linear regression with standardized scales (3), and treatment received by DSPs preferred treatment. Results: 2502 patients (68%) and 1203 eligible DSPs (70%) responded, resulting in 1,173 dyads, 292 where the patient identified as Latina, and 881 as non-Latina. Among Latina dyads, 78%, 17%, and 5% DSPs identified as Latinx, White, and Asian/Black/Other, respectively. Latinx DSPs within Latina/Latinx dyads were younger, had lower educational attainment and acculturation when compared to other dyads. The proportion of married/partnered status was not different across dyads, but the key DSP for the Latina-Latinx dyads was more often a daughter (37%), over a husband/partner (21%), compared to the other dyads. Latinx DSPs reported being more informed (adjusted mean 4.26, p = 0.058) compared to the other dyads, and being more informed was positively associated with higher patient SDQ (adjusted mean difference 0.176, p = 0.034), despite no difference in treatment deliberation. Overall, Latinx DSP had a higher preference for mastectomy, especially with reconstruction when compared to non-Latinx (40% vs 28%). Overall, 27% of Latinas (vs 13% non-Latina) underwent lumpectomy despite their DSP’s preference for mastectomy. Conclusions: These findings reveal that the key DSP for many married Latinas is often a daughter over spouse/partner. Our results suggest that including daughter/DSPs in treatment decisions and tailoring strategies to meet their information needs may positively impact Latina SDQ. Potential areas of improvement include surgical options preferences, where notable discrepancy was seen between Latinas and non-Latinas. Awareness of these differences can minimize treatment regret, improve decision quality, and ultimately outcomes in Latinas.
Engineered AAVs for non-invasive gene delivery to rodent and non-human primate nervous systems
Authors: Xinhong Chen, Sripriya Ravindra Kumar, Cameron D. Adams, Daping Yang, Tongtong Wang, Damien A. Wolfe, Cynthia M. Arokiaraj, Victoria Ngo, Lillian J. Campos, Jessica A. Griffiths, Takako Ichiki, Sarkis K. Mazmanian, Peregrine B. Osborne, Janet R. Keast, Cory T. Miller, Andrew S. Fox, Isaac M. Chiu, Viviana Gradinaru
Journal: Neuron (2022)

Gene therapy offers great promise in addressing neuropathologies associated with the central and peripheral nervous systems (CNS and PNS). However, genetic access remains difficult, reflecting the critical need for the development of effective and non-invasive gene delivery vectors across species. To that end, we evolved adeno-associated virus serotype 9 (AAV9) capsid in mice and validated two capsids, AAV-MaCPNS1 and AAV-MaCPNS2, across rodent species (mice and rats) and non-human primate (NHP) species (marmosets and rhesus macaques). Intravenous administration of either AAV efficiently transduced the PNS in rodents and both the PNS and CNS in NHPs. Furthermore, we used AAV-MaCPNS1 in mice to systemically deliver the following: (1) the neuronal sensor jGCaMP8s to record calcium signal dynamics in nodose ganglia and (2) the neuronal actuator DREADD to dorsal root ganglia to mediate pain. This conclusively demonstrates the translatability of these two systemic AAVs across four species and their functional utility through proof-of-concept studies in mice.
Topographical Mapping of the cardiac autonomic innervation for selective cardiac neuromodulation in pigs and rabbits using MicroCT
Authors: B Kronsteiner, L Zopf, P Heimel, G Oberoi, A-M Kramer, P Slezak, L Reissig, S Geyer, WJ Weninger, BK Podesser, A Kiss, F Moscato
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): Horizon 2020- EU H2020-EU.1.2.2. - FET Proactive "NeuHeart" Nr. 824071 Background &amp; Introduction In recent years, Vagus Nerve Stimulation (VNS) has proved to be a potential therapeutic approach for the treatment of cardiovascular diseases, such as Heart Failure or atrial fibrillation [1]. However, the lack of specific anatomical knowledge of the cervical VN [2, 3] and thus, of the cardiac autonomic innervation aggravates the side effects of unselective cervical VNS. Purpose The goal of this study was to investigate the cardiac vagus nerve branches for selective cardiac VNS stimulation using micro-computed tomography (µCT) and 3D renderings. Methods Vagus nerve specimens (n= 11 pig nerves, n= 5 rabbit nerves) were harvested from the nodose ganglion down to the cardiac branches in domestic pigs and New Zealand White rabbits on both sides, and the cardiac autonomic innervation was mapped µCT and 3D renderings. Results Our results provide anatomical and topographical key features on the cervical and cardiac autonomic innervation including course of the cardiac branch, cardiac branching patterns, fascicle number, and size of the autonomic nerves. We also compared these aforementioned anatomical parameters between pigs and rabbits and highlighted key anatomical differences among individuals within pigs. In pigs, the cardiac branches were partly composed of both nerves even when they branched off the VN whereas in rabbits, the two nerves were completely separated and the cardiac branch was solely parasympathetic. Finally, we generated a 3D model of various parts of the VN specimen and compared them to images of the native nerves taken during VN dissection surgery. Conclusions Here we present an imaging approach to map the anatomy and topography of the cardiac Vagus Nerve for selective stimulation of cardiac VN branches. We also characterized the morphology of the VN, the sympathetic trunk (ST), and the cardiac branch (CB) at the level of the cardiac branching point to highlight the complex interplay between the nerves. Our data provide one possible reason for unwanted side effects of cervical VNS. However, future studies are required to broaden the knowledge in this specific research field of selective cardiac VNS.
Preliminary findings of implementing the G8 screening tool in an academic cancer center.
Authors: Kuang-Yi Wen, Kristine Swartz, Tingting Zhan, Joseph Lombardo, Louis Cappelli, Ana Maria Lopez, Andrew E. Chapman
Journal: Journal of Clinical Oncology (2022)

12010 Background: Older patients often experience more toxicity from cancer treatments due to their functional age and co-morbidities. The G8 is a geriatric screening tool designed to identify patients who are appropriate for a comprehensive geriatric assessment (CGA) which will inform and optimize oncology therapeutic decision making, reduce toxicities and improve outcomes. Using a nurse-led assessment approach, we have implemented an EMR embedded G8 tool across our cancer center since June 2020. We aim to describe the characteristics of those patients who scored abnormal (≤ 14) on the G8. Methods: The demographic and clinical characteristics were collected from the EMR for those who were ≥ 65 and have completed the G8 screening tool from June 2020 to Jan 2022. Summary statistics such as means, standard deviations and proportions were reported. Comparisons of various endpoints between dichotomized (≤ 14 vs. &gt; 14) G8 scores were performed using pairwise two-sample t-test, pairwise proportion test, Fisher’s exact test and/or Pearson’s chi-squared test. Selected stakeholders were elicited for their perspectives on the implementation process. Results: 544 patients age ≥ 65 completed G8 screening with a mean score of 13.4 (± 2.3). The mean age was 75.2 (± 7.0), and 55.7% were females and 78.3% were non-Hispanic White. The most frequent cancer type was breast cancer (21.3%), followed by lung/respiratory cancer (18.2%), and GI cancer (15.8%). The percentage of patients appropriate for a CGA (based on an abnormal G8 score) was 59% (n = 332), of which only 10% (n = 31) were referred. A spearman correlation of 0.4 (p &lt; 0.001) between G8 scores and age was obtained. A statistically significant association between ECOG and G8 groups was found, but not for any comorbidities. The prevalence of current/former smoking and extreme polypharmacy (&gt; 10) is significantly higher in the G8 abnormal group. Implementation process evaluation found new patients with cancer overwhelmed with information, a lack of patient education and provider engagement, and an unstandardized referral process to CGA, were barriers for CGA referral. Conclusions: The G8 is an effective tool identifying patients appropriate for a CGA. An EMR embedded G8 steadily improved the G8 utilization uptake but not referral for CGA at our institution. To further improve awareness, utilization and referral, we are redesigning a hybrid workflow integrating patient-mediated MyChart implementation and nurse navigator engagement. EPIC enhancements are being designed to inform the oncologist of the patient’s G8 score, CGA referral status and the final CGA report.
A deep learning solution for detection of homologous recombination deficiency in ovarian cancer using low pass whole-genome sequencing: Evaluation of the analytical performance.
Authors: Adrien Buisson, Pierre Saintigny, Eric Pujade-Lauraine, Christine Montoto-Grillot, Davide Vacirca, Massimo Barberis, Nicoletta Colombo, Alexandre Harle, Pauline Gilson, Cristin Roma, Francesca Bergantino, Philipp Harter, Sandro Pignata, Antonio Gonzalez Martin, Christian Schauer, Keiichi Fujiwara, Ignace Vergote, Trine Jakobi Nøttrup, Pierre-Alexandre Just, Isabelle Laure Ray-Coquard
Journal: Journal of Clinical Oncology (2022)

e17599 Background: Poly (ADP-ribose) polymerase inhibitors (PARPi) induce synthetic lethality in cells with homologous recombination deficiency (HRD). PARPi treatment revolutionized management of patients with cancer, particularly in types where HRD is common, such as ovarian and breast cancer. However, challenges in the implementation of available methods currently limit adoption of HRD testing in the clinics. Here we present the analytical performance evaluation of the Genomic Integrity Index (GII) (SOPHiA GENETICs SA). Methods: GII is a deep-learning based solution for identification of HRD positive tumors from low-pass whole genome sequencing (lpWGS) data (X1 fold coverage). The analytical performance of the GII was evaluated as positive (PPA), negative (NPA) and overall (OPA) percentage of agreement with the HRD status determined by Myriad myChoice CDx (Myriad Genetic Laboratories, Inc.; US FDA-approved). We generated whole genome sequencing libraries for DNA extracted from 139 ovarian cancer Formalin-Fixed Paraffin- Embedded samples, in 4 independent clinical laboratories. We sequenced to the equivalent of 1X coverage (̃10 million reads, 150 base paired end reads, Illumina) and performed HRD classification data using GII using manufacturer’s recommended thresholds. Results: The GII demonstrated high analytical concordance with Myriad myChoice CDx with 91.7% PPA, 95.5% NPA and 94.5% OPA (Table). The HRD status obtained by GII from a subset of positive and negative samples was 100% reproducible (n = 4) between runs. Conclusions: The HRD status obtained by GII is highly concordant with that obtained from standard method, supporting that GII allows accurate and reproducible detection of HRD from lpWGS data. LpWGS is amongst the most cost-effective and easy to implement genome profiling methods, making it uniquely suited for clinical applications. [Table: see text]
A novel drug combination strategy that redesigns the pharmacological management of oral cancer.
Authors: Rajdeep Chakraborty, Charbel Darido, Honghua Hu, Karen Vickery, Shoba Ranganathan
Journal: Journal of Clinical Oncology (2022)

e18053 Background: Biofilm formation is a continuous process in oral cancer patients, despite proper extirpation/elimination of a bacterial plaque via a surgical procedure or antibiotic treatment. Also, elimination of a bacterial plaque does not necessarily remove extant bacterial antigen-stimulated oral cancer cells. Therefore, combination drug treatment may be an appropriate approach to elucidate the confounding effects of bacterial antigens on anti-cancer drugs. Methods: Our drug combination strategy addressed both Gram-positive (Lipoteichoic acid [LTA]) and Gram-negative (Lipopolysaccharide [LPS]) bacterial antigens, to determine the effect of anti-cancer drugs on LPS/LTA/LPS+LTA-stimulated preclinical oral cancer models (SCC4, SCC9, SCC25, and Cal 27). The drug combination strategy was designed in six phases of treatment. In phase 1, plated cells were treated with different combinations of bacterial antigens in combination with anti-cancer drugs. In the phases 2 and 3, inhibitory drugs were introduced in the presence of bacterial antigens after 24 hours and 72 hours of bacterial antigen stimulation. In phases 4 and 5, inhibitory drugs were added after 24 hours and 72 hours of bacterial antigen stimulation. In phase 6, inhibitory drugs were applied in the absence of, and without stimulation with, bacterial antigens. Metabolic assays, reverse transcription quantitative PCR, Western blot, Proteome Profiler, apoptotic and ELISA assays were performed to validate the novel drug combination strategy. Results: Anti-cancer drug treatment on preclinical oral cancer models resulted in 43.6% ± 3.3% of precancerous models being apoptotic. To mimic pre-existing unhygenic conditions in oral cancer patients, prior stimulation of preclinical model with LPS+LTA 72 hours before drug treatment, reduced apoptosis to 32.2% ± 1.1% of cells. Apoptosis was almost annulled (2.98% ± 0.3%; p &lt; 0.01) when drug treatment was carried out along with bacterial antigens. Treatment with drugs in the absence of bacterial antigens resulted in significantly more apoptotic cells than in presence of bacterial antigens (p &lt; 0.0001). Metabolic and viability assay showed similar results like apoptotic assay. Conclusions: Bacterial antigens mimic the presence of Gram-negative and Gram-positive bacteria and thus severely affect the efficacy of anti-cancer drugs. The novel drug combination strategy redesigns the pharmacological management of oral squamous cell carcinoma.
PARK7/DJ-1 promotes pyruvate dehydrogenase activity and maintains Treg homeostasis during ageing
Authors: Egle Danileviciute, Ni Zeng, Christophe M. Capelle, Nicole Paczia, Mark A. Gillespie, Henry Kurniawan, Mohaned Benzarti, Myriam P. Merz, Djalil Coowar, Sabrina Fritah, Daniela Maria Vogt Weisenhorn, Gemma Gomez Giro, Melanie Grusdat, Alexandre Baron, Coralie Guerin, Davide G. Franchina, Cathy Léonard, Olivia Domingues, Sylvie Delhalle, Wolfgang Wurst, Jonathan D. Turner, Jens Christian Schwamborn, Johannes Meiser, Rejko Krüger, Jeff Ranish, Dirk Brenner, Carole L. Linster, Rudi Balling, Markus Ollert, Feng Q. Hefeng
Journal: Nature Metabolism (2022)